One of the major causes of atherosclerosis and the related diseases, coronary heart disease (CHD), peripheral arterial disease (PAD), and cerebrovascular disease, is dyslipidemia. Dyslipidemia is an imbalance of each of the lipid components: total cholesterol (TC), high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and serum triglycerides.
Although it is still debated whether triglycerides have an indirect effect (via increased VLDL, decreased HDL, or enhancement of thrombogenesis) or direct effect on cardiovascular disease, there has been enough evidence accumulated in the last decade to consider high triglyceride serum levels to be independently related and important in measuring the risk of CHD (Austin et al., 1998, Am. J. Cardiol., 81: 7B-12B; Coughlan et al., 2000, Postgrad. Med., 108: 77-84; Rader et al., 2000, Med. Clin. North Am., 84: 43-61).
The PROCAM (The Prospective Cardiovascular Munster 1979-1985) study showed that fasting levels of triglycerides were an independent risk factor for CHD when excessive triglycerides are paired with high LDL and low HDL levels (Assmann et al., 1992, Am. J. Cardiol., 70: 733-737). The chance of a major coronary event was statistically significantly decreased with lowered triglyceride levels (Assmann et al., 1992). The Copenhagen Male Study also confirmed the results of the PROCAM study (Jeppesen et al., 1998, Circulation , 97: 1029-1036). The 3000 participant study showed that men who had triglyceride levels in the upper third region were 2.2 times more likely to be at risk of developing CHD (Jeppesen et al., 1998).
Normal fasting levels of triglyceride levels are 150 mg/dL and lower (National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), 2002, Circulation, 106:3143-3421). The range of 150 mg/dL to 199 mg/dL is considered borderline high, and levels greater than 200 mg/dL are high (NCEP Expert Panel, 2002). For borderline patients, non-pharmacologic measures are prescribed. This is usually a change in lifestyle including increased exercise, low fat diet and smoking cessation. When levels of triglycerides are greater than 200 mg/dL, drug treatment is given.
Hypertriglyceridemia may be classified as either primary or acquired (Assmann, et al., 1991, Am. J. Cardiol., 68: 13A-16A; Mancini et al., 1991, Am. J. Cardiol., 68: 17A-21A). Primary hypertriglyceridemias are inherited disorders, which include chylomicronemia (type I hyperlipoproteinemia), type V hyperlipoproteinemia, type III hyperlipoproteinemia (remnant hyperlipidemia or familial dysbetalipoproteinemia), familial hypertriglyceridemia, familial combined hyperlipidemia, and hepatic lipase deficiency (Assmann et al., 1991). The severity of the symptoms depends in part on whether the patient is homozygous or heterozygous. Primary hypertriglyceridemias may present as early as childhood. Acquired hypertriglyceridemia may be attributed to many factors, including metabolic disorders such as type II diabetes, metabolic syndome, insulin resistance, pre-diabetes, syndrome X, obesity, hyperuricemia, Alström's syndrome, and type I glycogen storage disease (Kreisberg, 1998, Am. J. Cardiol., 82: 67U-73U; Schmidt et al., 1996, Metabolism , 45: 699-706; Paisey et al., 2004, Clin. Endocrinol., 60: 228-231; Greene et al., 1991, J Pediatr., 119: 398-403). These conditions may also present in childhood. Similarly, hormonal disturbances may cause hypertriglyceridemia. In addition to insulin, triglyceride levels may be elevated as a result of hypothyroidism or polycystic ovary syndrome (Kvetny et al., 2004, Clin. Endocrinol., 61: 232-238; Pirwany et al., 2001, Clin. Endocrinol., 54: 447-453).
Acquired hypertriglyceridemia can be due to lifestyle factors such as diet (high sugar or carbohydrate intake) or alcohol consumption (Coughlan et al., 2000). Chronic disease states such as renal disease (including nephrotic syndrome and renal failure) or paraproteinemia can also cause elevated triglycerides (Attman et al., 1997, Contrib. Nephrol., 120:1-10; Oda et al., 1998, Nephrol. Dial. Transplant., 13:45-49; Matteucci et al., 1996, Clin. Rheumatol., 15:20-24.). These disorders may also manifest in childhood. Finally, a number of different drugs can raise triglyceride levels (Drug Ther Perspect, 2001, 17:11-15; Mantel-Teeuwisse et al., 2001, Drug Saf., 24:443-456), including diuretics (including thiazide (Lindholm et al., 2003, J. Hypertens., 21:1563-1574) and loop diuretics (van der Heijden et al., 1998, J. Clin. Pharmacol., 38:630-635); β-blockers (Fogari et al., 1989, J. Cardiovasc. Pharmacol., 14:S28-S32); angiotensin converting enzyme inhibitors (Ravid et al., 1995, Kidney Int., 47:907-910); estrogen replacement therapy (Miller et al., 1994, Obstet. Gynecol., 83:173-179.); oral contraceptives with second and third generation progestogens (Scharnagl et al., 2004, Contraception, 69:105-113; Gaspard et al., 2004, Contraception., 69:271-278); estrogen receptor modulators (such as tamoxifen (Elisaf et al., 2000, Ann. Oncol., 11: 1067-1069)); retinoids (such as isotretinoin (Zech et al., 1983, Arch. Dermatol., 119:987-993) and acitretin (Vahlquist et al., 1988, Acta Derm. Venereol., 68:300-305)); immunosuppressive drugs (such as rapamycin (Groth et al., 1999, Transplantation, 67:1036-1042)); protease inhibitors (such as ritonavir (Mirete et al., 1998, Eur. J. Clin. Microbiol. Infect. Dis., 17:810-811), indinavir (Roberts et al., 1999, Clin. Infect. Dis., 29:441-443) and nelfinavir (Di Martino et al., 1999, AIDS, 13:1421-1423)); and antipsychotics (such as clozapine (Gaulin et al., 1999, Am. J. Psychiatry, 156: 1270-1272)).
The three main treatment options for hypertriglyceridemia are statins, fibrates, and niacin. While statins are the most commonly prescribed drug for hyperlipidemia, they are not usually given unless the patient also has high LDL levels. Statins only give a marginal (10-30%) reduction in triglycerides. This decrease is dependent on the type of statin given. Nicotinic acid gives better reductions in triglycerides than statins. On average, a 20% to 40% reduction of triglycerides can be seen with low doses of niacin. Side effects from niacin include mild to moderate flushing and hyperglycemia and hepatic toxicity with higher doses. These side effects prevent niacin from being suitable for a large population, especially diabetics. Fibrates are the most effective triglyceride lowering agents. The average reduction with fibrate treatment is 20% to 55%. The major side effect of fibrates is gastrointestinal discomfort, which occurs in up to 10% of patients.
Current lipid lowering therapies do not sufficiently address the high triglyceride levels that are now known to be an important risk factor for cardiovascular disease without unwanted side effects.